Eukaryotic initiation factor

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Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an important input for post-transcription gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNA iMet called the 43S preinitiation complex (43S PIC). Additional factors of the eIF4F complex (eIF4A, E, and G) recruit the 43S PIC to the five-prime cap structure of the mRNA, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes gated phosphate and eIF1 release to form the 48S preinitiation complex (48S PIC), followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. [1] There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below. [2]

Contents

eIF1 and eIF1A

eIF1 and eIF1A both bind to the 40S ribosome subunit-mRNA complex. Together they induce an "open" conformation of the mRNA binding channel, which is crucial for scanning, tRNA delivery, and start codon recognition. [3] In particular, eIF1 dissociation from the 40S subunit is considered to be a key step in start codon recognition. [4] eIF1 and eIF1A are small proteins (13 and 16 kDa, respectively in humans) and are both components of the 43S PIC. eIF1 binds near the ribosomal P-site, while eIF1A binds near the A-site, in a manner similar to the structurally and functionally related bacterial counterparts IF3 and IF1, respectively. [5]

eIF2

eIF2 is the main protein complex responsible for delivering the initiator tRNA to the P-site of the preinitiation complex, as a ternary complex containing Met-tRNA iMet and GTP (the eIF2-TC). eIF2 has specificity for the methionine-charged initiator tRNA, which is distinct from other methionine-charged tRNAs used for elongation of the polypeptide chain. The eIF2 ternary complex remains bound to the P-site while the mRNA attaches to the 40s ribosome and the complex begins to scan the mRNA. Once the AUG start codon is recognized and located in the P-site, eIF5 stimulates the hydrolysis of eIF2-GTP, effectively switching it to the GDP-bound form via gated phosphate release. [2] The hydrolysis of eIF2-GTP provides the conformational change to change the scanning complex into the 48S Initiation complex with the initiator tRNA-Met anticodon base paired to the AUG. After the initiation complex is formed the 60s subunit joins and eIF2 along with most of the initiation factors dissociate from the complex allowing the 60S subunit to bind. eIF1A and eIF5B-GTP remain bound to one another in the A site and must be hydrolyzed to be released and properly initiate elongation. [6] : 191–192 

eIF2 has three subunits, eIF2-α, β, and γ. The former α-subunit is a target of regulatory phosphorylation and is of particular importance for cells that may need to turn off protein synthesis globally as a response to cell signaling events. When phosphorylated, it sequesters eIF2B (not to be confused with eIF2β), a GEF. Without this GEF, GDP cannot be exchanged for GTP, and translation is repressed. One example of this is the eIF2α-induced translation repression that occurs in reticulocytes when starved for iron. In the case of viral infection, protein kinase R (PKR) phosphorylates eIF2α when dsRNA is detected in many multicellular organisms, leading to cell death.

The proteins eIF2A and eIF2D are both technically named 'eIF2' but neither are part of the eIF2 heterotrimer and they seem to play unique functions in translation. Instead, they appear to be involved in specialized pathways, such as 'eIF2-independent' translation initiation or re-initiation, respectively.

eIF3

eIF3 independently binds the 40S ribosomal subunit, multiple initiation factors, and cellular and viral mRNA. [7]

In mammals, eIF3 is the largest initiation factor, made up of 13 subunits (a-m). It has a molecular weight of ~800 kDa and controls the assembly of the 40S ribosomal subunit on mRNA that have a 5' cap or an IRES. eIF3 may use the eIF4F complex, or alternatively during internal initiation, an IRES, to position the mRNA strand near the exit site of the 40S ribosomal subunit, thus promoting the assembly of a functional pre-initiation complex.

In many human cancers, eIF3 subunits are overexpressed (subunits a, b, c, h, i, and m) and underexpressed (subunits e and f). [8] One potential mechanism to explain this disregulation comes from the finding that eIF3 binds a specific set of cell proliferation regulator mRNA transcripts and regulates their translation. [9] eIF3 also mediates cellular signaling through S6K1 and mTOR/Raptor to effect translational regulation. [10]

eIF4

The eIF4F complex is composed of three subunits: eIF4A, eIF4E, and eIF4G. Each subunit has multiple human isoforms and there exist additional eIF4 proteins: eIF4B and eIF4H.

eIF4G is a 175.5-kDa scaffolding protein that interacts with eIF3 and the Poly(A)-binding protein (PABP), as well as the other members of the eIF4F complex. eIF4E recognizes and binds to the 5' cap structure of mRNA, while eIF4G binds PABP, which binds the poly(A) tail, potentially circularizing and activating the bound mRNA. eIF4A –a DEAD box RNA helicase  –is important for resolving mRNA secondary structures.

eIF4B contains two RNA-binding domains –one non-specifically interacts with mRNA, whereas the second specifically binds the 18S portion of the small ribosomal subunit. It acts as an anchor, as well as a critical co-factor for eIF4A. It is also a substrate of S6K, and when phosphorylated, it promotes the formation of the pre-initiation complex. In vertebrates, eIF4H is an additional initiation factor with similar function to eIF4B.

eIF5, eIF5A and eIF5B

eIF5 is a GTPase-activating protein, which helps the large ribosomal subunit associate with the small subunit. It is required for GTP-hydrolysis by eIF2.

eIF5A is the eukaryotic homolog of EF-P. It helps with elongation and also plays a role in termination. EIF5A contains the unusual amino acid hypusine. [11]

eIF5B is a GTPase, and is involved in assembly of the full ribosome. It is the functional eukaryotic analog of bacterial IF2. [12]

eIF6

eIF6 performs the same inhibition of ribosome assembly as eIF3, but binds with the large subunit.

See also

Related Research Articles

Bacterial translation is the process by which messenger RNA is translated into proteins in bacteria.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.

The Kozak consensus sequence is a nucleic acid motif that functions as the protein translation initiation site in most eukaryotic mRNA transcripts. Regarded as the optimum sequence for initiating translation in eukaryotes, the sequence is an integral aspect of protein regulation and overall cellular health as well as having implications in human disease. It ensures that a protein is correctly translated from the genetic message, mediating ribosome assembly and translation initiation. A wrong start site can result in non-functional proteins. As it has become more studied, expansions of the nucleotide sequence, bases of importance, and notable exceptions have arisen. The sequence was named after the scientist who discovered it, Marilyn Kozak. Kozak discovered the sequence through a detailed analysis of DNA genomic sequences.

In molecular biology, initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.

A bacterial initiation factor (IF) is a protein that stabilizes the initiation complex for polypeptide translation.

<span class="mw-page-title-main">Hepatitis C virus internal ribosome entry site</span>

The Hepatitis C virus internal ribosome entry site, or HCV IRES, is an RNA structure within the 5'UTR of the HCV genome that mediates cap-independent translation initiation.

<span class="mw-page-title-main">EIF1AX</span> Protein-coding gene in humans

Eukaryotic translation initiation factor 1A, X-chromosomal (eIF1A) is a protein that in humans is encoded by the EIF1AX gene. This gene encodes an essential eukaryotic translation initiation factor. The protein is a component of the 43S pre-initiation complex (PIC), which mediates the recruitment of the small 40S ribosomal subunit to the 5' cap of messenger RNAs.

<span class="mw-page-title-main">EIF5B</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 5B is a protein that in humans is encoded by the EIF5B gene.

<span class="mw-page-title-main">EIF1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 1 (eIF1) is a protein that in humans is encoded by the EIF1 gene. It is related to yeast SUI1.

The eukaryotic small ribosomal subunit (40S) is the smaller subunit of the eukaryotic 80S ribosomes, with the other major component being the large ribosomal subunit (60S). The "40S" and "60S" names originate from the convention that ribosomal particles are denoted according to their sedimentation coefficients in Svedberg units. It is structurally and functionally related to the 30S subunit of 70S prokaryotic ribosomes. However, the 40S subunit is much larger than the prokaryotic 30S subunit and contains many additional protein segments, as well as rRNA expansion segments.

Eukaryotic translation initiation factor 4 G (eIF4G) is a protein involved in eukaryotic translation initiation and is a component of the eIF4F cap-binding complex. Orthologs of eIF4G have been studied in multiple species, including humans, yeast, and wheat. However, eIF4G is exclusively found in domain Eukarya, and not in domains Bacteria or Archaea, which do not have capped mRNA. As such, eIF4G structure and function may vary between species, although the human EIF4G1 has been the focus of extensive studies.

Eukaryotic Initiation Factor 2 (eIF2) is an eukaryotic initiation factor. It is required for most forms of eukaryotic translation initiation. eIF2 mediates the binding of tRNAiMet to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer consisting of an alpha, a beta, and a gamma subunit.

The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that function to unwind double-stranded RNA.

<span class="mw-page-title-main">Eukaryotic ribosome</span> Large and complex molecular machine

Ribosomes are a large and complex molecular machine that catalyzes the synthesis of proteins, referred to as translation. The ribosome selects aminoacylated transfer RNAs (tRNAs) based on the sequence of a protein-encoding messenger RNA (mRNA) and covalently links the amino acids into a polypeptide chain. Ribosomes from all organisms share a highly conserved catalytic center. However, the ribosomes of eukaryotes are much larger than prokaryotic ribosomes and subject to more complex regulation and biogenesis pathways. Eukaryotic ribosomes are also known as 80S ribosomes, referring to their sedimentation coefficients in Svedberg units, because they sediment faster than the prokaryotic (70S) ribosomes. Eukaryotic ribosomes have two unequal subunits, designated small subunit (40S) and large subunit (60S) according to their sedimentation coefficients. Both subunits contain dozens of ribosomal proteins arranged on a scaffold composed of ribosomal RNA (rRNA). The small subunit monitors the complementarity between tRNA anticodon and mRNA, while the large subunit catalyzes peptide bond formation.

Translational regulation refers to the control of the levels of protein synthesized from its mRNA. This regulation is vastly important to the cellular response to stressors, growth cues, and differentiation. In comparison to transcriptional regulation, it results in much more immediate cellular adjustment through direct regulation of protein concentration. The corresponding mechanisms are primarily targeted on the control of ribosome recruitment on the initiation codon, but can also involve modulation of peptide elongation, termination of protein synthesis, or ribosome biogenesis. While these general concepts are widely conserved, some of the finer details in this sort of regulation have been proven to differ between prokaryotic and eukaryotic organisms.

<span class="mw-page-title-main">Eukaryotic initiation factor 3</span> Multiprotein complex that functions during the initiation phase of eukaryotic translation

Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation. It is essential for most forms of cap-dependent and cap-independent translation initiation. In humans, eIF3 consists of 13 nonidentical subunits (eIF3a-m) with a combined molecular weight of ~800 kDa, making it the largest translation initiation factor. The eIF3 complex is broadly conserved across eukaryotes, but the conservation of individual subunits varies across organisms. For instance, while most mammalian eIF3 complexes are composed of 13 subunits, budding yeast's eIF3 has only six subunits.

<span class="mw-page-title-main">Eukaryotic initiation factor 4F</span> Multiprotein complex used in gene expression

Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the 5' cap of messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-identical subunits: the DEAD-box RNA helicase eIF4A, the cap-binding protein eIF4E, and the large "scaffold" protein eIF4G. The mammalian eIF4F complex was first described in 1983, and has been a major area of study into the molecular mechanisms of cap-dependent translation initiation ever since.

The 43S preinitiation complex is a ribonucleoprotein complex that exists during an early step of eukaryotic translation initiation. The 43S PIC contains the small ribosomal subunit (40S) bound by the initiation factors eIF1, eIF1A, eIF3, and the eIF2-Met-tRNAiMet-GTP ternary complex (eIF2-TC).

<span class="mw-page-title-main">DHX29</span> Protein-coding gene in the species Homo sapiens

DExH-box helicase 29 (DHX29) is a 155 kDa protein that in humans is encoded by the DHX29 gene.

Archaeal initiation factors are proteins that are used during the translation step of protein synthesis in archaea. The principal functions these proteins perform include ribosome RNA/mRNA recognition, delivery of the initiator Met-tRNAiMet, methionine bound tRNAi, to the 40s ribosome, and proofreading of the initiation complex.

References

  1. ↑ Jackson RJ, Hellen CU, Pestova TV (February 2010). "The mechanism of eukaryotic translation initiation and principles of its regulation". Nature Reviews Molecular Cell Biology. 11 (2): 113–27. doi:10.1038/nrm2838. PMC   4461372 . PMID   20094052.
  2. 1 2 Aitken CE, Lorsch JR (June 2012). "A mechanistic overview of translation initiation in eukaryotes". Nature Structural & Molecular Biology. 19 (6): 568–76. doi:10.1038/nsmb.2303. PMID   22664984. S2CID   9201095.
  3. ↑ Passmore LA, Schmeing TM, Maag D, Applefield DJ, Acker MG, Algire MA, Lorsch JR, Ramakrishnan V (April 2007). "The eukaryotic translation initiation factors eIF1 and eIF1A induce an open conformation of the 40S ribosome". Molecular Cell. 26 (1): 41–50. doi: 10.1016/j.molcel.2007.03.018 . PMID   17434125.
  4. ↑ Cheung YN, Maag D, Mitchell SF, Fekete CA, Algire MA, Takacs JE, Shirokikh N, Pestova T, Lorsch JR, Hinnebusch AG (May 2007). "Dissociation of eIF1 from the 40S ribosomal subunit is a key step in start codon selection in vivo". Genes & Development. 21 (10): 1217–30. doi:10.1101/gad.1528307. PMC   1865493 . PMID   17504939.
  5. ↑ Fraser CS (July 2015). "Quantitative studies of mRNA recruitment to the eukaryotic ribosome". Biochimie. 114: 58–71. doi:10.1016/j.biochi.2015.02.017. PMC   4458453 . PMID   25742741.
  6. ↑ Lodish H, Berk A, Kaiser CA, Krieger M, Bretscher A, Ploegh H, Amon A, Martin KC (2016). Molecular Cell Biology (8th ed.). New York: W. H. Freeman and Company. ISBN   978-1-4641-8339-3. LCCN   2015957295.
  7. ↑ Hinnebusch AG (October 2006). "eIF3: a versatile scaffold for translation initiation complexes". Trends in Biochemical Sciences. 31 (10): 553–62. doi:10.1016/j.tibs.2006.08.005. PMID   16920360.
  8. ↑ Hershey JW (July 2015). "The role of eIF3 and its individual subunits in cancer". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1849 (7): 792–800. doi:10.1016/j.bbagrm.2014.10.005. PMID   25450521.
  9. ↑ Lee AS, Kranzusch PJ, Cate JH (June 2015). "eIF3 targets cell-proliferation messenger RNAs for translational activation or repression". Nature. 522 (7554): 111–4. Bibcode:2015Natur.522..111L. doi:10.1038/nature14267. PMC   4603833 . PMID   25849773.
  10. ↑ Holz MK, Ballif BA, Gygi SP, Blenis J (November 2005). "mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events". Cell. 123 (4): 569–80. doi: 10.1016/j.cell.2005.10.024 . PMID   16286006.
  11. ↑ Schuller, AP; Wu, CC; Dever, TE; Buskirk, AR; Green, R (20 April 2017). "eIF5A Functions Globally in Translation Elongation and Termination". Molecular Cell. 66 (2): 194–205.e5. doi:10.1016/j.molcel.2017.03.003. PMC   5414311 . PMID   28392174.
  12. ↑ Allen GS, Frank J (February 2007). "Structural insights on the translation initiation complex: ghosts of a universal initiation complex". Molecular Microbiology. 63 (4): 941–50. doi: 10.1111/j.1365-2958.2006.05574.x . PMID   17238926.

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